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Proposal for individualized dosing of eculizumab in atypical haemolytic uraemic syndrome: patient friendly and cost-effective

2022; Oxford University Press; Volume: 38; Issue: 2 Linguagem: Inglês

10.1093/ndt/gfac056

1460-2385

Mendy ter Avest, Romy N. Bouwmeester, Caroline Duineveld, Kioa L. Wijnsma, Elena B. Volokhina, Lambertus P. van den Heuvel, David M. Burger, Jack F.M. Wetzels, Nicole C. A. J. van de Kar, Rob ter Heine, E van Kempen, Wim Altena, Eddy Adang, Dirk Jan A. R. Moes, A.D. van Zuijlen, Stefan P. Berger, F. J. Bemelman, Joost W van der Heijden, J. van de Wetering, Aiko P. J. de Vries, P van Paasen, Jack F.M. Wetzels, J. A. E. van Wijk, Antonia H. Bouts, Eiske M. Dorresteijn, Valentina Gracchi, Flore A. P. T. Engels, Mandy G. Keijzer‐Veen, R W G van Rooij, Nicole C. A. J. van de Kar,

Erythrocyte Function and Pathophysiology

Eculizumab is a lifesaving yet expensive drug for atypical haemolytic uraemic syndrome (aHUS). Current guidelines advise a fixed-dosing schedule, which can be suboptimal and inflexible in the individual patient.We evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) [classical pathway (CP) activity levels] of eculizumab in 48 patients, consisting of 849 time-concentration data and 569 CP activity levels. PK-PD modelling was performed with non-linear mixed-effects modelling. The final model was used to develop improved dosing strategies.A PK model with parallel linear and non-linear elimination rates best described the data with the parameter estimates clearance 0.163 L/day, volume of distribution 6.42 L, maximal rate 29.6 mg/day and concentration for 50% of maximum rate 37.9 mg/L. The PK-PD relation between eculizumab concentration and CP activity was described using an inhibitory Emax model with the parameter estimates baseline 101%, maximal inhibitory effect 95.9%, concentration for 50% inhibition 22.0 mg/L and Hill coefficient 5.42. A weight-based loading dose, followed by PK-guided dosing was found to improve treatment. On day 7, we predict 99.95% of the patients to reach the efficacy target (CP activity <10%), compared with 94.75% with standard dosing. Comparable efficacy was predicted during the maintenance phase, while the dosing interval could be prolonged in ∼33% of the population by means of individualized dosing. With a fixed-dose 4-week dosing interval to allow for holidays, treatment costs will increase by 7.1% and we predict 91% of the patients will reach the efficacy target.A patient-friendly individualized dosing strategy of eculizumab has the potential to improve treatment response at reduced costs.